title: RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.
authors.affiliation: Department of Neuropathology, Graduate School of Medicine.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ihara
authors.forename: Koji
authors.initials: K
authors.lastname: Matsukawa
authors.forename: Yusei
authors.initials: Y
authors.lastname: Nagata
authors.forename: Hayato
authors.initials: H
authors.lastname: Kunugi
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Takahiro
authors.initials: T
authors.lastname: Chihara
authors.forename: Erina
authors.initials: E
authors.lastname: Kuranaga
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009410:Nerve Degeneration; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D012313:RNA